Adjuvant nivolumab versus placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274.

The phase III randomized, double-blind, multicenter CheckMate 274 trial comparing adjuvant nivolumab versus placebo in patients with high-risk MIUC after radical surgery demonstrated that adjuvant nivolumab improved disease-free survival (DFS) versus placebo.

III期随机、双盲、多中心的CheckMate 274试验比较了高危MIUC患者在根治性手术后使用辅助性纳武利尤单抗与安慰剂的效果，结果表明辅助性纳武利尤单抗相比安慰剂能改善无病生存期（DFS）。

We report results with 5-year minimum follow-up including exploratory analyses of circulating tumor DNA (ctDNA).

我们报告了包括循环肿瘤DNA (ctDNA) 探索性分析在内的5年最短随访结果。

patients_and_methods

Eligible patients had radical surgery (R0, with negative surgical margins) within 120 days before being randomized, with or without neoadjuvant cisplatin-based chemotherapy.

符合条件的患者在随机分组前120天内接受了根治性手术（R0，手术切缘阴性），无论是否接受新辅助顺铂化疗。

Overall, 709 patients with MIUC at high risk of recurrence after surgery were randomly assigned 1:1 to nivolumab 240 mg or placebo every 2 weeks for ≤1 year.

总体而言，709名高复发风险的肌肉浸润性尿路上皮癌（MIUC）术后患者按1:1的比例随机分配接受每2周240毫克的纳武利尤单抗或安慰剂治疗，最长不超过1年。

The primary endpoint was DFS.

主要终点是无病生存期（DFS）。

Overall survival(OS) was a key secondary endpoint.

总生存（OS）是关键次要终点。

In a post hoc exploratory analysis, baseline ctDNA was measured using the Signatera assay.

在事后探索性分析中，使用Signatera检测法测量了基线循环肿瘤DNA（ctDNA）。

Results

Median DFS was 21.9 months [95% confidence interval(CI) 18.8-36.9 months] with nivolumab versus 11.0 months (95% CI 8.3-16.6 months) with placebo in all randomized patients [hazard ratio(HR) 0.74, 95% CI 0.61-0.90], and 55.5 months (95% CI 25.8-66.5 months) versus 8.4 months (95% CI 5.6-20.0 months) in patients with tumor programmed death-ligand 1 expression ≥1% (HR 0.58, 95% CI 0.42-0.79).

在所有随机患者中，中位无进展生存期（DFS）为21.9个月（95%置信区间[CI] 18.8-36.9个月）使用纳武利尤单抗，而使用安慰剂的为11.0个月（95% CI 8.3-16.6个月），风险比（HR）为0.74（95% CI 0.61-0.90）。在肿瘤程序性死亡配体1（PD-L1）表达≥1%的患者中，中位DFS为55.5个月（95% CI 25.8-66.5个月）使用纳武利尤单抗，而使用安慰剂的为8.4个月（95% CI 5.6-20.0个月），HR为0.58（95% CI 0.42-0.79）。

In all randomized patients, median OS was 75.0 months (95% CI 56.7 months-not estimable) with nivolumab versus 50.1 months (95% CI 38.0-72.1 months) with placebo (HR 0.83, 95% CI 0.67-1.02).

在所有随机患者中，中位总生存期（OS）为75.0个月（95% CI 56.7个月-无法估计）使用纳武利尤单抗，而使用安慰剂的为50.1个月（95% CI 38.0-72.1个月），风险比（HR）为0.83（95% CI 0.67-1.02）。

Baseline ctDNA after radical surgery was detected in 54 (40.6%) of 133 assessable patients.

在133名可评估的患者中，有54名（40.6%）在根治性手术后检测到基线循环肿瘤DNA（ctDNA）阳性。

Median DFS was 52.1 months (95% CI 19.4 months-not estimable) versus 5.0 months (95% CI 2.8-6.5 months) in patients with undetectable versus detectable ctDNA at baseline (HR 0.30, 95% CI 0.18-0.48).

基线ctDNA不可检测的患者与可检测的患者的中位无病生存期（DFS）分别为52.1个月（95%置信区间19.4个月-无法估计）和5.0个月（95%置信区间2.8-6.5个月）（风险比HR 0.30，95%置信区间0.18-0.48）。

In patients included in the ctDNA analysis who had detectable ctDNA, the median DFS HR for nivolumab-treated patients versus placebo-treated patients was 0.35 (95% CI 0.18-0.66), while in patients with undetectable ctDNA, the HR for nivolumab-treated patients versus placebo-treated patients was 0.99 (95% CI 0.51-1.93).

在纳入ctDNA分析的患者中，ctDNA可检测的患者中，接受纳武单抗治疗的患者的中位无病生存期（DFS）风险比（HR）为0.35（95%置信区间0.18-0.66），而在ctDNA未检测到的患者中，接受纳武单抗治疗的患者的HR为0.99（95%置信区间0.51-1.93）。

There were no new safety signals.

没有出现新的安全信号。

Conclusions

Five-year results confirm durable DFS benefit and consistent safety profile for adjuvant nivolumab in high-risk MIUC.

五年的研究结果证实，辅助性纳武利尤单抗在高危肌肉浸润性尿路上皮癌中具有持久的无病生存期（DFS）益处和一致的安全性特征。

Post hoc exploratory ctDNA assessment identified patients at highest risk of recurrence and may inform tailored adjuvant therapy strategies, pending further validation.

事后探索性的循环肿瘤DNA（ctDNA）评估识别出复发风险最高的患者，这可能有助于制定个性化的辅助治疗策略，但需要进一步验证。